TW200812578A - Use of CRFI receptor antagonists for preparing a drug for treating metabolic syndrome and/or obesity and/or dyslipoproteinemia - Google Patents

Abstract

An object of the present invention is the use of a compound of formula (I): or one of its pharmaceutically acceptable salts, for the manufacture of a medicament for the prevention and/or the treatment of metabolic syndrome and/or obesity and/or dyslipoproteinemia.

Description

200812578 IX. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to the use of an aminothiazole derivative for the preparation of a medicament for the prophylactic or therapeutic treatment of metabolic syndrome and/or obesity and/or abnormal lipoprotein gold. [Prior Art] European Patent η. ΕΡ 1 200 419 describes an amine thiazole derivative of formula (I) as a CRF! antagonist:

Wherein - R and R2 which may be the same or different each independently represent a halogen atom; a base group (Ci_Cs); (Ci_C; 5) a base; an aryl moiety (C6-Cs) and a burnt moiety (Ci-) C4) aralkyl; (Ci-C5) alkoxy; trifluoromethyl; nitro; nitrile; R represents hydrogen, (Ci-C 5) alkyl or wherein the aryl moiety is (C6-C8) And the alkyl moiety is a group of the aralkyl group of (CVC4)-SR; R represents (Ci-CO alkyl or an aralkyl group in which the aryl moiety is (C6-C8) and the alkyl moiety is (CVC4) The group -S-CO-R; Ra represents a hydrogen or a (Ci-Cs) alkyl group -COORa; Ra and Rb are as defined above for Ra -CONRaRb; Ra and Rb are as defined above for Ra a group -NRaRb; wherein Rc and Rd and the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic group 119126.doc 200812578 -CONRcRd or -NRcRd; or Ra and Rb are as defined above for Ra-NHCO-NRaRb - R3 represents hydrogen or as defined above in 1 and 1^2; or, when R3 is substituted at the 5-position with a phenyl group, r2 and 3 constitute a group in which χ independently represents CH2 or an oxygen or sulfur atom _x_Cii2_x_; -R6 represents (CVC6) alkyl; (Ci-CJ alkoxyalkyl; (C3-C5) ring burned (C3-C6) cycloalkyl (Ci-C6) alkyl; (Ci-C6) sulfur-based (c^c3) alkyl; (CVC6) alkylthio (CVC3) alkyl; (Ci -Cdalkylthiodioxy(CVC3)alkyl; -R7 represents unsubstituted, halogen, calcined, oro-CHyO- group at the 3, 4 or 5 position in the phenyl group Adjacent to a carbon atom, via -CF3, -N〇2 or -CN, via Rs and & represents ((: 143) alkyl group _ (300 尺 8 or -CONR8R9 or via group _Ch2 上R8, which represents a phenyl group which is mono-, di- or tri-substituted with R1G of the CrCO alkyl group; or represents a pyridyl group, a thienyl group, a carbazolyl group, an imidazolyl group, a (C3_C5) cycloalkyl group or (c3-c6) a cycloalkyl (CVC6) alkyl group; an addition salt thereof, a hydrate thereof and/or a solvate thereof. EP i 200 419 also describes a compound of the formula (1) for use in the preparation of a prophylactic or curative treatment for a stress-related disorder And more specifically, the use of agents for the following conditions: Cushing, s disease, neuropsychiatric suspension, such as depression, anxiety, panic, obsessive-compulsive disorder, affective disorder, post-traumatic stress disorder, behavioral disorder, Aggressive, anorexia, bulimia , hyperglycemia, premature birth, risky pregnancy, growth and pain, sleep disorders, epilepsy and all types of depression; Alzheimer's disease (Alzheimer, s "Call, Pa 119126.doc 200812578 Parkinson's disease" , Huntington's ch〇rea; amyotrophic lateral sclerosis; vascular, cardiac and cerebral disorders; sexual behavior disorder and fertility disorders; immunosuppression, immune suppression, inflammatory processes, multiple infections, Rheumatoid arthritis, bones, inflammation, uveitis, psoriasis and diabetes; cancer; gastrointestinal dysfunction • Inflammation caused by it, such as irritable and inflammatory bowel, diarrhea; pain disorder, p muscle fiber pain associated with or without sleep disorders, fatigue or migraine; symptoms associated with alcohol dependence and discontinuation of the drug. It has now been found that the compound of the formula (I) is therapeutically effective as an active ingredient for the prophylactic or curative treatment of metabolic syndrome and/or obesity and/or abnormal lipoprotein blood. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to use a compound of formula (1) for the manufacture of a medicament for the prophylactic or curative treatment of metabolic syndrome and/or obesity and/or abnormal lipoprotein blood. 〇 Metabolic Syndrome, also known as Syndrome X, covers the complex symptoms of carbohydrate and eclipse metabolism, characterized by obesity, abnormal lipoprotein blood (low HDL and high LDL, VLDL and triglycerides), hyperinsulinemia , insulin resistance, glucose intolerance and high blood pressure (Ather〇scler〇sis x? Fp Woodford, J. Davignon, A. Sniderman(^) ? Elsevier

Science BV, Amsterdam (1995) 520-524). Syndrome X appears to be the cause of the energy imbalance. The main underlying risk factors for this syndrome appear to be abdominal obesity and insulin resistance. Insulin resistance is a systemic metabolic disorder in which the body cannot effectively use insulin. For these reasons, 119126.doc 200812578 This metabolic syndrome is also known as insulin resistance syndrome. To date, there is no widely accepted standard for diagnosing metabolic syndrome. However, the standard proposed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) is recommended and widely used today: patients with metabolic syndrome exhibit at least three criteria for the following criteria: obesity, dyslipidemia, hypertension, and high Glucose.

The American Heart Association and the National Heart, Lung, and Blood Institute recommends that metabolic syndrome be converted to three or more parameters with the following parameters: • Waist circumference increase: Male: equal to or greater than 40吋 (102 cm) Female: equals Or greater than 35 吋 (88 cm) • Triglyceride increase: equal to or greater than 150 mg/dL • HDL (“good'') cholesterol reduction: Male: less than 40 mg/dL Female: less than 50 mg/dL • Increased blood pressure : equal to or greater than 130/85 mm Hg • fasting glucose increase: equal to or greater than 100 mg/dL. One of the objects of the invention is a compound of formula (I): 119126.doc 200812578

Wherein - R and R2 which may be the same or different each independently represent a halogen atom; a hydroxy (CVC5) alkyl group; (cvc5) alkyl group, an aryl moiety (c6-c8) and an alkyl moiety (CrC4) Alkyl; (Ci-Cs) alkoxy; trifluoromethyl; nitro; nitrile; R represents hydrogen, (C^-Cs)alkyl or wherein the aryl moiety is (C6-C8) and the alkyl moiety Is (Ci-CJ aralkyl group -SR; R represents (CrCs) alkyl or wherein the aryl moiety is (C6-C8) and the alkyl moiety is ((VCO aralkyl group -S) -CO-R ; Ra represents a hydrogen or (CrCs) alkyl group -COORa; Ra and Rb are as defined above for Ra -CONRaRb; Ra and Rb are as defined above for Ra -NRaRb; wherein Rc And a group in which the nitrogen atom to which R is attached constitutes a 5- to 7-membered heterocyclic ring -CONRcRd or -NRcRd; or Ra and Rb are as defined in the above-mentioned Ra-NHCO-NRaRb; -R3 represents hydrogen or as above 1^ And 112 is defined; or, when R3 is substituted for a phenyl group at the 5-position, 112 and r3 constitute a group wherein X independently represents CH2 or an oxygen or sulfur atom _X_CH2-X-; -R6 represents (CrCO alkyl; CVCd alkoxy (CrCO alkyl; (C3-C5) cycloalkyl; (C3-C6) cycloalkyl (C i-CJ alkyl; (Ci-CO alkylthio (CV C3) alkyl (Ci_C6) alkylthio (Ci_C3) alkyl; (Ci_C6) alkyl 119126.doc 200812578 thiodioxy (CkCs )alkyl;

-R? represents unsubstituted, at the 3, 4 or 5 position via halogen, via (c^c5) alkyl, via -O-CHyO- group on two adjacent carbon atoms of the phenyl group, via -CF3 , -N〇2 or _CN, by: ^ and! ^ represents a group of (Ci_C3)alkyl groups -coor84 -conr8r9 or a phenyl group which is mono-, di- or tri-substituted by a group of _CH2〇r8, wherein (R1G represents a (Q-C5) alkyl group; or & represents pyridine , thiophenyl, pyrazolyl, imidazolyl, (C3_C5)cycloalkyl or (c3-c6)cycloalkyl (CVC6)alkyl; addition salts thereof, hydrates thereof and/or solvates thereof, The use of a medicament intended for the prophylactic or curative treatment of metabolic syndrome. The compound of formula (1), either in the form of the free base or in the form of an acid addition salt, may also be provided as part of the present invention. The compound of formula (1) may contain one or more asymmetric carbon atoms. Thus it may exist in enantiomeric or diastereomeric forms. Such enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, form part of the present invention. The compound of formula (I) may be in the form of a hydrate or solvate, i.e., in association or combination with one or more water or solvent molecules. According to the invention, the following terms have the following meanings: 'and t and z may contain from 1 to carbon atoms - the halogen atom corresponds to a fluorine, gas, bromine or iodine atom; - (Ct-Cz) represents a chain or a ring, It may have 1 to 2 carbon atoms representing an integer selected from 1 to 10. For example, (Ci - c3) represents a chain of three slave atoms, and (C3_C6) represents 3 to 6 119126.doc 200812578 rings; - an alkyl group corresponds to a saturated, linear or branched aliphatic group. The following examples can be cited: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl; -cycloalkyl corresponding to cyclic alkyl. The following examples may be cited: cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; -alkoxy corresponding to -0-alkyl, wherein alkyl is as defined above; -hydroxyalkyl Corresponding to an alkyl group in which one or more hydrogen atoms are substituted by a hydroxyl group; - an aryl group corresponding to an aromatic, cyclic group such as a phenyl group containing 5 to 6 carbon atoms; - an aryl group corresponding to The substituted aryl group on the alkyl chain. For example, benzyl. Another embodiment of the present invention relates to the use of a compound of the formula (1), an addition salt thereof, a hydrate thereof and/or a solvate thereof for the manufacture of a medicament for the prophylactic or curative treatment of metabolic syndrome, wherein - the same Or different hearts and 2 independently represent a halogen atom; (Ci_c5) alkyl; (Ci-C5) alkoxy; -R3 represents hydrogen or as defined above and ^^; -R6 represents (Ci-CJ (Cl_c6) alkoxy group (Ci_c3); (C3_C5) cycloalkyl; (C3-C6) cycloalkyl (Cl_c6) alkyl; _ R7 is not unsubstituted or in the 3 or 4 position Halogen, (Ci_C5)alkyl, wherein Rs represents (the group of CrCd alkyl group _Ch2〇r8 or phenyl group which is mono- or disubstituted by _〇_Ch2-Ο- group at positions 3 and 4; or (C3_c5)cycloalkyl. 119126.doc 200812578 Another embodiment of the present invention relates to a compound of the formula (I) wherein 3 is at the 5-position of the substrate, an addition salt thereof, and a water bastard thereof. / or a solvate thereof for use in the manufacture of a medicament for prophylactic or phlegm-reducing pain. The use of a medicament for the metabolic syndrome of Yizhuang/Oral therapy 0. Another embodiment of the present invention relates to the formula ω The compound, its addition salt, its hydrate and/or its solvate are used for the manufacture of a medicament for the prophylactic or curative treatment of metabolic syndrome (4), and the compound of the formula (1) is selected from

/ , V / -[4-(2-chloro-4_methoxy_5_methylphenyl)_5_methylthiazole_2_yl][(ir)_ (ι-(3ϋmethylphenyl) _2_methoxyethyl)]propan-2-ynylamine hydrochloride, _[4-(2-chloro-4_decyloxy-5-methylphenyl)_5-methylthiazole_ 2_yl][(ls)_(1-phenylbutyl)]propan-2-ynylamine hydrochloride, -[4·(2-chloro-4-methoxy-5-mercaptobenzene) -5-methylthiazol-2-yl n(lS)-(2-cyclopropyl-1_phenylethyl)]propan-2-ynylamine hydrogenate, -[4-(2- Chloro-4-methoxyphenyl)·5-methylthiazol-2-yl][(lS)-(2-cyclopropyl-1-benylethyl)]propan-2-furanyl hydrogen acid Salt, -[4-(2-Ga-4-methoxy-5-mercaptophenyl)-5-methylthiazol-2-yl][(is)-(2-cyclopropyl-1-( 4-fluorophenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazole -2-yl][(is)-(1-phenylpentyl)]prop-2-ynylamine hydrogenate, -[4-(2- gas-4-methoxy-5-mercaptobenzene) _5-Mercaptothiazol-2-yl][(1R)_(2-methoxy-1-(4-methoxyindolylphenyl)ethyl)]prop-2-ynylamine Hydrogen Salt, 119126.doc -12- 200812578 -[4-(2-Ga-4-methoxy-5-methylbenzene )_5_Methyloxazol-2-yl][(1 S)-(1-(4-methoxyindolylphenyl)pentyl)]propan-2-ynylamine hydrochloride, -[ 4-(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazole-2-yl][(1S)-(1-(4-fluorophenyl)pentyl)] Prop-2-ynylamine hydrochloride, -[4-(2-gas-4.methoxy-5-methylphenyl)-5-mercaptopurin-2-yl][(1S) -(cyclopropylphenylindenyl)]prop-2-ynylamine hydrogenate, -[4-(2- gas-4-oximeoxy-5-methylphenyl)-5-methyloxime嗤-2-yl][(18)_(1-(3-IL-4-methylphenyl)pentyl)]prop-2-ynylamine hydrochloride, -[4-(2-gas 4-methoxy-5-nonylphenyl)-5-fluorenyl 0-plug. Sodium-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]propan-2-hexylamine hydrochloride

fXM salt, -[4-(2- gas-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(is)-(1-(4-fluorophenyl) Butyl)]prop-2-ynylamine hydrochloride, -[4-(2·Ga-4-methoxy-5-methylphenyl)·5·methylindol-2-yl ][(1S)-(1-(3-Fluoro-4-methoxyindolylphenyl)butyl)]prop-2-ynylamine Hydrogenate, -[4-(2-Ga-4- Nonyl-5-nonylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-chlorophenyl)ethyl)]propane-2 - fast-chain amine hydrogenate, -[4-(2- gas-4-methoxy-5-methylphenyl)-5-mercaptothiazole-2_yl][(1S)-(2-ί Aceyl-1-(4-mercaptophenyl)ethyl)]propan-2-mercaptoamine Hydrogenate, -[4-(2-Ga-4-methoxy-5-methylphenyl) )_5-methylindol-2-yl][(18)-(2-cyclobutyl-1-(4-fluorophenyl)ethyl)]prop-2-ynylamine hydrochloride, - [4-(2-Ga-4-methoxy-5-mercaptophenyl)-5-methylthiazol-2-yl][(1S>(2-cyclopropyl-1-(4-bromobenzene) Ethyl)]prop-2-ynylamine Hydrogenate, -[4-(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl] [(1S)- 119126.doc -13 - 200812578 (2-cyclopropyl 4-(3,4-methylenedioxyphenyl)B )]propan-2-alkynylamine hydrochloride, -[4-(2- ox-4-methoxyphenyl)_5-methylthiazol-2-yl][(lS)-(2-ring Propyl 4-(3-fluoro-4-mercaptophenyl)ethyl)]prop-2-ynylamine hydrogenate, -[4_(2,4-dimethoxy-5-methylphenyl) )-5-methylthiazole-2-yl][(1S)-(2-cyclopropylfluoro-4-methylphenyl)ethyl)]prop-2-ynylamine hydrochloride, -[ 4-(4-Methoxy-2,5-dimethylphenyl)_5-methylthiazol-2-yl][(1S)-(2-cyclopropyl4-(3-fluoro-4-methyl) Phenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazole-2_ Base][(18)-(1-(3,4-Methylenedioxyphenyl)butyl)]propan-2-ynylamine hydrogenate. Another embodiment of the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the prophylactic or curative treatment of metabolic syndrome, wherein the compound is [4-(2-chloro-4-methoxy-) 5-methylphenyl)-5-methylthiazol-2-yl][USH2-cyclopropylfluoro-4-ylphenyl)ethyl)]propan-2-ynylamine hydrochloride. Another object of the invention is a compound of formula (I):

Its hydrate and/or its solvate is used for the manufacture of a medicament intended to pre-treat the additive salt 119126.doc •14- 200812578 for the prevention or treatment of obesity, wherein - the same or different 1^ and 112 Each independently represents a halogen atom; a hydroxy (Ci-Cs) alkyl group; (CVC5) alkyl group; an aryl moiety is (c0_c8) and an alkyl moiety is a (C1-C4) square alkyl group; (C1-C5) is burned. Oxyl, dimurazinyl; schlossyl; nitrile; R represents hydrogen, (C^Cs)alkyl or a group wherein the aryl moiety is ((VC8) and the alkyl moiety is (CVCU) aralkyl- SR; R represents a (CrC5) alkyl group or a group -S-CO-R wherein the aryl moiety is (C6-C8) and the alkyl moiety is (CVC4) aralkyl; Ra represents hydrogen or (CVCs) alkane a group of the group -COORa; Ra and Rb are as defined above for Ra -CONRaRb; Ra and Rb are as defined above for Ra -NRaRb; wherein Rc and Rd are bonded to the nitrogen atom to which they are 5 to 7 members a heterocyclic group -CONRcRd or -NRcRd; or a group of Ra and Rb as defined above for Ra-NHCO-NRaRb; -R3 represents no hydrogen or as defined by Ri and R2 above; or 'when R3 is substituted at position 5 In the case of phenyl, r2 and chemistry 3 constitute X-individual The site represents CH2 or the oxygen or sulfur atom group -X-CH2-X-; -R6 represents (CVC6), (CKC6) alkoxyalkyl; (C3_C5) cycloalkyl; (C3-C6) ring (CVC6) alkyl; (Cl-c6) sulfur-based (Ci-C3) alkyl; (VC6) alkylthio (Cl-C3) alkyl; (Ci_c6) alkylthiodioxy a group of (Ci_C3) alkyl groups; -R7 represents unsubstituted, at the 3, 4 or 5 position via a _ s, a (Ci_C5) alkyl group, and a 2-CH2-0- group at the two adjacent phenyl groups a group on the carbon atom, via -CF3, -N〇2 or -CN, via its center and R9 (Ci_c3), 119126.doc 200812578 group -C00R4 _c〇NR8R9 or via group _CH2〇r8, Ri〇 represents a (Ci-C5) alkyl group of 0R1 mono-, di- or tri-substituted phenyl; or R7 represents a pyridine group, a thienyl group, a carbazolyl group, an imidazolyl group, a (C3_C5) cycloalkyl group or (c3- C6) a cycloalkyl (Cl_c6) alkyl group. Another embodiment of the present invention relates to a compound of the formula (1), an addition salt thereof, a hydrate thereof and/or a solvate thereof for use in the manufacture of a prophylactic or curative treatment The use of an obesity agent, wherein - the same or different 1 and 2 independently represent a halogen (Ci_c5) alkyl; (CVC5) alkoxy; -R3 represents hydrogen or as defined above for 1^ and 112; -R6 represents (CVC6) fluorenyl; (CVC6) alkoxy (Ci-Cs) alkyl (C3-C5) cycloalkyl; ((VC6)cycloalkyl(CVC6)alkyl; -R7 represents unsubstituted or at the 3 or 4 position via halogen, alkyl, wherein R8 represents (CVC3) alkyl The group -CH2OR8 or a phenyl group which is mono- or disubstituted by the _〇_CH2- 〇- group at the 3, 4 position; or r7 represents a (C3_C5) cycloalkyl group. Another embodiment of the present invention relates to a compound of the formula (1) wherein 5 is at the 5-position of the phenyl group, and an addition salt thereof, a hydrate thereof and/or a solvate thereof for use in the manufacture of a medicament for the prophylactic or curative treatment of obesity The use of the medicament. Another embodiment of the present invention relates to the use of a compound of the formula (1), an addition salt thereof, a hydrate thereof and/or a solvate thereof for the manufacture of a medicament for the prophylactic or curative treatment of obesity, a compound of the formula (1) Is selected from: -[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)- 119126.doc -16 - 200812578 ( 1-(3-Fluoro-4-methylphenyl)-2-methoxyethyl)]propan-2-ynylamine hydrochloride, -[4-(2- gas-4-methoxy -5-methylphenyl)-5-methylthiazol-2-yl][(1S)_(1-phenylbutyl)]prop-2-ynylamine hydrogenate, -[4-(2 - gas · 4 · decyloxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]propane_2 _ alkynylamine hydrogenate, -[4-(2- gas-4-methoxyphenyl)-5-methylthiazol-2-yl][(lS)-(2-cyclopropyl-1- Phenylethyl)]prop-2-ynylamine hydrochloride, • [4-(2-Ga-4-methoxy-5(nonylphenyl)-5methylthiazol-2-yl] [(1S)-(2-cyclopropyl-1-(4-fluorophenyl)ethyl)]propan-2-ynylamine hydrogenate, -[4_(2- gas-4-methoxy- 5-methylphenyl)_5-methylthiazol-2-yl][(1S)-(1-phenylpentyl)] 2-Alkynylamine Hydrogenate, -[4-(2-Ga-4-methoxy-5-methylphenyl)-5.methylthiazol-2-yl][(1R)· (2 -methoxy-1-(4-methoxymethylphenyl)ethylpropynylamine hydrochloride, • [4-(2·chloro-4-methoxy-5-methylphenyl) -5-mercaptothiazol-2-yl][(1S)-0-(4-methoxymethylphenyl)pentyl)]propynylamine hydrochloride, β [4·(2- Chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-fluorophenyl)pentyl)]prop-2-ynylamine hydrogenate, -[4-(2-Ga-4-oximeoxy-5-methylphenyl)-5-methyloxime-indole_2-yl][(1S)-(cyclopropylphenylmethyl)] Prop-2-ynylamine hydrogenate, -[4-(2-chloro-4-methoxy-5-methylphenyl)-5.methylhydrazine. Sodium-2-yl][(1S)-0-(3-fluoro-4-methylphenyl)pentyl)]prop-2-ynylamine hydrogenate, _ [4-(2-chloro-4) -methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-119126.doc -17- 200812578 (2-cyclopropyl-1-(3-fluoro-4-) Methylphenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylcarbazole -2-yl][(is)-(1-(4-fluorophenyl)butyl)]prop-2-ynylamine hydrochloride, -[4-(2-chloro-4-methyllactyl) -5-methylphenyl)-5-methylindole-2-yl][(is)_(1-(3-fluoro-4-methoxymethylphenyl)butyl)]propane-2 - alkynylamine hydrogenate, -[4-(2- gas-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(is)_ (2-ring Propyl-1-(4-(phenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2-chloro-4-methoxy-5-methylphenyl) -5-methyl σ s- s- yl-2-[]is ((is)_(2-cyclopropyl-1-(4-methylphenyl)ethyl)]prop-2-ynylamine chlorate -[4-(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(is)-(2-cyclobutyl-1-(4) -fluorophenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2-chloro-4.methoxy-5-methylphenyl) -5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-bromophenyl)ethyl)]prop-2-ynylamine hydrochloride, -[ 4-(2-Chloro-4-methoxy-5-mercaptophenyl)-5-methylthiazol-2-yl n(lS)_ (2-3⁄4propyl-1-(3,4-A) Methyldioxyphenyl)ethyl)]propan-2-mercaptoamine hydrochloride, -[4-(2-chloro-4-methoxyphenyl)-5-methyl. -2 -yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine hydrochloride--[ 4-(2,4-Dimethoxy-5-methylphenyl)-5-methylthiazol-2-yl(13)_(2-cyclopropyl-1-(3·fluoro-4-) Methylphenyl)ethyl)]propynylamine hydrochloride, _[4-(4-methoxy-2,5-diamidinophenyl)-5-methylthiazol-2-yl] [(18)-(2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine gas 119126.doc -18 - 200812578 salt, - [4. (2-Chloro-4.methoxy-5-methylphenyl)_5-methylindole-2-yl] (1-(3,4-methylenedioxyphenyl) Base)] C 2 - block amine amine nitrogenate.

A further embodiment of the invention relates to the use of a compound of formula (1) for the manufacture of a medicament intended for the prophylactic or curative treatment of obesity*, wherein the compound is [4_(2_chloro-4-I_methoxy_5_A) Phenyl phenyl) 1 methyl thiazole 2 _ kechuan (8) · (2) cyclopropyl-rn4 · methyl phenyl) ethyl)] propan-2-yl block amine hydrochloride. Another object of the invention is a compound of formula (1):

7 (l) the use of an addition salt, a hydrate thereof and/or a solvate thereof for the manufacture of a medicament for the prophylactic or curative treatment of abnormal lipoprotein blood,

Wherein - the same or different 1 and R2 each independently represent a halogen atom; the base (C1-C5)alkyl group (Ci-C5) is alkyl, the aryl moiety is (c6_c8) and the alkyl moiety is (C) "C4" arylalkyl; (Ci-C5) alkoxy; trifluoromethyl; nitro, nitrile; R represents hydrogen, (Ci-C5) alkyl or wherein the aryl moiety is (C6_C8) and burned The group r of the aryl group of the (Ci-CU) group represents a (Ci-C5) alkyl group or a group in which the aryl moiety is (c^c: 8) and the alkyl moiety is (C1-C4). The group -S-CO-R; Ra represents a hydrogen or (Ci-C) group-COORa; Ra and Rb are as defined above Ra, 119126.doc -19-200812578 -CONRaRb; Ra and Rb are as defined above for Ra-NRaRb; wherein Rc and Rd and the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic group -CONRcRd or -NRcRd; or Ra and Rb are as defined above for Ra a group -NHCO-NRaRb; -R3 represents hydrogen or as defined above; and when 'R3 is substituted at the 5-position with a phenyl group, RjR3 constitutes a group wherein X independently represents CH2 or an oxygen or sulfur atom -X-ch2-X-; -R6 represents (C1-C6)alkyl; (Ci-C6)alkoxy(CrCs)alkyl; (c3_c 5) w % cycloalkyl; (C3-C6) cycloalkyl (cvc6) alkyl; (cKC6) alkylthio (CV c3) alkyl; (CVC6) alkyl thio (Ci-Cs) alkyl (Ci_C6)alkylthiodioxy(CVC3)alkyl; -R7 represents unsubstituted, halogen, (Ci-Cs) alkyl, via-O-CH^O at the 3, 4 or 5 position a group on the two adjacent carbon atoms of the phenyl group, via -cf3, -no24-cn, via a group in which r8&r9 represents a (Ci-c3)alkyl group - (: 00118 or -CONR8R9 or a thiol group) a group -CH2〇R8, wherein R10 represents a phenyl group of a mono-, di- or tri-substituted R1G of a {) (Cl-C5) alkyl group; or r7 represents a pyridyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, (C3- C5) cycloalkyl or (c3-c6)cycloalkyl (CVC6)alkyl. Another embodiment of the invention relates to a compound of formula (1), an addition salt thereof, a hydrate thereof and/or a solvate thereof The use of an agent for the prophylactic or curative treatment of aberrant lipoprotein gold, wherein · the same or different cores and 2 independently represent a _ atom; an alkyl group; (CVC5) alkoxy group; -R3 Represents hydrogen or as defined above and 2; 119126.doc 20- 200812578 -R6 means (CVC 6) alkyl; (CVC6) alkoxy (CVC3) alkyl; (c3-c5) cycloalkyl; (c3-c6) cycloalkyl (CVC6) alkyl; -R7 means unsubstituted or at 3 or a 4-position halogen- or (Ci-Cs)-alkyl group, wherein R8 represents a group of (CVC3) alkyl group -CH2OR8 or a phenyl group which is mono- or di-substituted at the 3, 4-position via -0-CH2-indenyl; Or r7 represents a (C3-C5)cycloalkyl group. Another embodiment of the present invention relates to a compound of the formula (I) wherein 113 is at the 5-position of the phenyl group, and an addition salt thereof, a hydrate thereof and/or a solvate thereof, for use in the manufacture of a prophylactic or curative treatment The use of an abnormal lipoprotein agent. Another embodiment of the present invention relates to the use of a compound of the formula (I), an addition salt thereof, a hydrate thereof and/or a solvate thereof for the manufacture of a medicament for the prophylactic or curative treatment of abnormal lipoprotein blood, The compound of the formula (I) is selected from the group consisting of: -[4·(2- gas-4-oximeoxy-5-methylphenyl)-5.methylthiazol-2-yl][(1R)-( 1-(3-Fluoro-4-methylphenyl)-2-methoxyethyl)]propan-2 - fast-chain amine hydrochloride, -[4-(2- gas-4-methoxy -5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylbutyl)]prop-2-ynylamine hydrochloride, -[4-( 2-ox-4-methoxy-5-methylphenyl)·5-mercaptothiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethylpropynylamine Hydrochloride, -[4-(2-Ga-4-methoxyphenyl)-5-methylthiazol-2-yl][(lS)-(2-cyclopropyl-1-phenylethyl) Base]]prop-2-ynylamine hydrogenate, -[4-(2- gas-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S )-(2-3⁄4propyl-1-(4-fluorophenyl)ethyl)]propan-2-hydrogenamine hydrogenate, 119126.doc -21 - 200812578 β [4-(2-gas-4) -methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(IS)-(1-benzene Butyl)]prop-2-ynylamine Hydrogenate, -[4-(2-Ga-4-methoxy-5-methylphenyl)_5-methylthiazol-2-yl][(1R )-(2-methoxy-1-(4-methoxymethylphenyl)ethyl)]propan-2-ynylamine hydrochloride, -[4-(2-gas-4-A) Oxy-5-nonylphenyl)-5-mercaptothiazol-2-yl n(lS)-(1-(4-methoxymethylphenyl)pentyl)]propan-2-ynylamine Hydrochloride, -[4-(2-Ga-4-methoxy-5-methylphenyl)·5-methylthiazol-2-yl][(1S)-(1-(4- gas Phenyl)pentyl)]propan-2-mercaptoamine Hydrogenate, -[4-(2-Ga-4-methoxy-5-mercaptophenyl)-5-mercaptothiazol-2-yl ][(1S)-(cyclopropylphenylmethyl)]prop-2-ynylamine hydrochloride, -[4-(2- gas-4-decyloxy-5-methylphenyl) -5-mercaptothiazol-2-yl][(1S)-(1-(3-fluoro-4-methylphenyl)pentyl)]prop-2-ynylamine hydrogenate, -[4- (2-Ga-4-decyloxy-5-mercaptophenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4- Nonylphenyl)ethyl)]prop-2-ynylamine Hydrogenate, -[4-(2-Ga-4-methoxy-5-nonylphenyl)-5-mercaptothiazole-2 -yl][(1S)-(1-(4-fluorophenyl)butyl)]prop-2-ynylamine hydrochloride, -[4-(2-Ga-4-methoxy-5-mercaptophenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-oxime) Methylphenyl)butyl)]prop-2-ynylamine hydrochloride-[4-(2-chloro-4-methoxy-5-nonylphenyl)-5-methylthiazole -2-yl][(1S)-(2-cyclopropyl-1-(4-chlorophenyl)ethyl)]prop-2-ynylamine hydrogenate' -[4-(2-gas- 4-methoxy-5-mercaptophenyl)-5-mercaptothio<-2-yl n(lS)_(2-cyclopropyl-1-(4-mercaptophenyl)ethyl) ]prop-2-ynylamine hydrogenate' 119126.doc -22- 200812578 -[4-(2-Ga-4-methoxy-5-methylphenyl)-5-mercaptothiazole-2- Base][(IS)-(2-cyclobutyl-i_(4-fluorophenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2_氯_4_甲甲Oxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl4-(4-bromophenyl)ethyl)]prop-2-yne Base amine hydrochloride, -[4-(2-gas-4-methoxy-5-methylphenyl)-5-methyl alpha succinyl][()-(2-cyclopropyl _i_(3,4-Methylenedioxyphenyl)ethyl)]prop-2-ynylamine hydrochloride, [4-(2-chloro-4-methoxyphenyl)-5 -methylthiazol-2-yl][(lS)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)] 2-alkynylamine hydrochloride, -[4-(2,4-dimethoxy-5-nonylphenyl)-5-methylthiazol-2-yl][(18)-( -cyclopropyl-丨兴^Fluoro-demethylmethyl hydrazine ethyl" propyl--alkynylamine hydrogenate, -[4-(cardiomethoxy-2,5-didecylphenyl) A Thiazole-2-yl h(1s)_(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine hydrogenate, -[4 -(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3,4-methylenedioxybenzene) Butyl)]propan-2-ynylamine hydrogenate. Another embodiment of the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the prophylactic or curative treatment of aberrant lipoprotein blood, wherein the compound is [4-(2-gas-4-methoxy) 5-(nonylphenyl)-5-methylthiazol-2-yl][(lS)-(2-cyclopropylfluoro-4-methylphenyl)ethyl)]propan-2-ynyl Amine hydrochloride. The present invention relates to a method for the prophylactic or curative treatment of metabolic syndrome and/or obesity and/or abnormal lipoprotein blood, the method comprising administering at least one of a therapeutically effective amount of 119126.doc -23-200812578 to a mammal a compound of formula (1). The preparation and characteristics of the compounds of the formula (1) of the present invention are described in European Patent No. EP-A-200-419. The compound of the present invention is subjected to pharmacological studies (determination of physiological parameters), and the nature of the compound and its use as a therapeutic active substance f, that is, for the treatment and prevention of new metabolic syndrome and/or obesity and/or abnormality The value of lipoproteinemia. More specifically, the compound of the formula (1) has been tested to detect the effect on some physiological parameters and energy balance. The properties of the compound of the formula (1) have been investigated by pharmacologically known one group of animal tests. For example, hereditary obesity (9)/mediated ZuAa rats are one of the most investigated obesity models. Mutagenesis prevents the expression of long isoforms of isofin receptors (phiUips et al., Nat Genet. 1996; 13: 18-19), which mediates the anorexia and heat production of leptin . Rats are characterized by immature obesity, which occurs early in life, due to increased food intake and regulation of fever. In addition, it has high U-lipidemia, high insulin blood, glucose intolerance and insulin resistance. It also has a very high amount of corticosterone due to excessive stimulation of the hypothalamic pituitary-adrenal (HPA) axis (Guillaume-Gentil et al, Endocrinology 1990; 126: • 1873-1879) and when faced with stressful experimental conditions (eg Excessive expression of cortisol releasing factor (CRF) in fasting) (Guillaume-Gentil et al., 1990; 126: 1873-1879; Timofeeva and Richard, J. Comp. Neurol. 1997; 441·· 71-89) ° One of the compounds of the present invention, [4_(2_chloro-4-yloxy-5-methylphenyl)-5-methylthiazol-2-yl][(lS)-(2-cyclopropyl- 1-(3-Fluoro-4-methylphenyl) 119126.doc -24 - 200812578 Ethyl]]prop-2-ynylamine Hydrogenate (=Compound A) was subjected to the following tests 1 and 2 〇 [Embodiment Materials and Methods 1. Rats used in the experiment purchased 8-9 weeks old thin (Fa/?) and obese (/·α//α) male Zucker large from Charles River Laboratories (St-Constant, QC). mouse. According to Canadian

Guide for the Care and Use of Laboratory Animals All rats were approved and the agreement was approved by the University Laval animal care committee. Throughout the study, rats were given a diet of refined high-water-resistant compounds consisting of the following substances (expressed in g/Ι 〇〇g): 31.2 corn starch, 31·2 DL-dextrose, 6.4 soybean oil, 20.0 Casein, 0.3 DL-methionine, 1.0 vitamin mixture (Teklad no. 40060; Teklad, Madison, Wl), 4.9 AIN-93 mineral mixture (ICN Biochemicals, Montreal, QC) and 5.0 fiber (Alphacel; ICN Biochemicals) . The energy content of the food is 64.9% carbohydrate, 14.5% fat and 20.6% egg.

The LJ is white in composition and has a density of 4.01 kcal/g. Rats were subjected to a 12 h/12 h dark/light cycle (light between 07 h00 and 19 h00 and dark between 19 h00 and 07 h00) and maintained at 23 ° 1 °C ambient temperature. Treated rats received either oral administration of Compound A twice daily for 21 days; 10 mg/kg at 08h30 and 20 mg/kg at 16h00. On the last day of treatment, 30 mg/kg of Compound A was administered and sacrificed 4 hours later. Rats were weighed daily during the experiment and the food intake was measured. Kill 119126.doc -25- 200812578 rats between 14h00 and 17h00 in random feeding or after 6 hours of fasting. Thin and obese rats were anesthetized with 2 and 4 ml of a mixture containing 20 mg/ml ketamine and 2.5 mg/ml dioxanilide xylazine. Blood was collected by intra-cardiac puncture into a syringe coated with 〇55 ethylenediaminetetraacetic acid (EDTA; Sigma-Aldrich, St. Louis, MO) and the rats were perfused with ice-cold isotonic saline for 2 minutes. . 2. Preparation of a solution containing Compound A to be administered Compound A was suspended in 0.6% methylcellulose containing 0.5% Tween 80 during the first 14 days of treatment, and suspended in 5% DMSO during the last 7 days of treatment ( Dimethyl sulfoxide), 5% hexadecanol polyoxyethylene ether EL, 90% saline 0. Test 1: Measurement of body energy, fat and protein increase The cadaver was autoclaved at 125 kPa for 15 minutes to soften Hard tissue, this procedure has been reported to not affect energy production (Lofti et al. 1976). The cadaveric energy content was determined by adiabatic thermal calorimetry using 250-300 mg dehydrated cadaver, and cadaveric protein was determined using a FP-2000 Nitrogen Analyser (Leco corporation, St. Joseph, MI). The energy of the non-protein material is obtained by subtracting the protein energy from the total corpse energy. Since carbohydrates represent a negligible fraction of total corpse energy (Webster 1983), it is assumed that non-protein material energy is primarily derived from fat. The energy content of protein and fat was calculated using values of 23.5 and 39.2 kj/g, respectively (Webster 1983). The initial energy, fat and protein content of the cadaver were estimated from the in vivo weight of the weak and obese rats by reference to the rat baseline group killed at the experimental period. This estimate allows for an assessment of the amount of energy, fat, and protein added during the treatment period. Rats in the baseline group (six per phenotype) were killed in the energy balance test, and the energy of each animal's corpse was analyzed. Protein 119126.doc -26- 200812578 and monthly fat and average energy density (per gram)胄Heavy energy kilocalories) protein starter (mother grams of body weight protein grams) and fat density (grams of fat per gram of body weight). The average density was multiplied by the initial body weight of each rat assigned to the experimental group. The rats in the initial group were identical to the rats in the experimental group (e.g., age and sex). Food efficiency is expressed as the ratio of the amount of energy increase to the amount of energy that can be taken or subtracted by 1 〇 〇. 4. Test 2: Plasma determination

Blood was collected by cardiac puncture, centrifuged (1500 g, 15 minutes at 4 °C) and the plasma separated at -20 °C until later biochemical amount. Use automatic glucose analyzer YSI 2300 stat Plus (YSI

Incorporated, Yellow Springs, OH) measures plasma glucose concentration. Plasma triacetin was assayed using a commercially available enzyme kit (R〇che Diagn〇stics) that calibrates free glycerol. Plasma insulin and leptin levels were determined using a commercially available radioimmunoassay kit (Linc® Research, St. Charles, MO). Use a commercially available radioimmunoassay kit (MP Biomedicals, Toronto, ON) (J 疋 疋 疋 。 。 。 。. Use a commercially available enzyme kit (Wako Diagnostics,

Richmond, VA) characterizes plasma non-esterified fatty acids (NEFA). 5. Statistical results are expressed as one of the mean ± standard deviations (SE). Statistical analysis of the daily food intake and cumulative weight gain between each of the genotype-based controls and the test compound A-treated rats was determined by repeated measures analysis of variance (RM-ANOVA) using a mixed model analysis. The cumulative weight gain data was logarithmically transformed and the multivariate normality was verified using Mardia's test. The cadaver analysis of each genotype was determined by Student's test (Student's /-test) 119126.doc -27- 200812578 and ΗΟΜΑ-IR results were statistically different. Statistical differences in all other variables within each genotype were determined by two-way analysis of variance (AN0VA). In order to comply with the normal assumption, the data of corticosterone, insulin and triglyceride were logarithmically converted. All two-factor ANOVAs were subsequently tested by Tukey's multiple comparison test. The P value <〇·〇5 is considered to be the result. RM, ANOVA was performed using the SAS ν9·1·3 software package (SAS Institute, Cary, NC), and other statistical analyses were performed using SigmaStat v2.0 software (SPSS, Chicago, IL). The results of tests 1 and 2 (points 3 and 4) are illustrated by the following figures. Figure 1. Daily food intake (a) and cumulative body weight in Zucker rats with thin (Fa/?) and hereditary obesity (/a//a) during daily oral administration of 30 mg/kg Compound A for 20 days. Increase the amount (b). * Corpse <0·〇5, π = 14/group. Figure 2. Total energy increase (a), protein increase in thin (Fa/?) and hereditary obesity (/b//a) Zucker rats after oral administration of 30 mg/kg compound daily for 20 days. (b), fat increase (c) and food efficiency percentage (d). * If the Student/Test Assessment is handled significantly. P < 0.05, n = 7 per group. Figure 3. Thin (Fa/?) and hereditary obesity (/a//a) in random silver food (AL) and 6-hour fasting (FD) after oral administration of 30 mg/kg of Compound A per day for 20 days. Plasma triglyceride (a), non-esterified fatty acid (NEFA) (b), corticosterone (c), glucose (d), and insulin (e) in Zucker rats. In vivo balance model assessment (HOMA-IR) for insulin resistance in FD rats was calculated using glucose and insulin measurements (f). The significant main effect of treatment* and the significant main effect of sputum fasting (ΗΟΜΑ-IR) as assessed by the two-factor ANOVA or ί test. When significant, only the interaction results (bars) of the phase 119126.doc -28- 200812578 as assessed by the Taki multi-factor comparison test are shown. Ρ <〇·〇5, ":=6-7·· groups. Figures la, lb, 2.a, 2, 2, and 2 (1) The results of test i were summed. Treatment with Compound A significantly reduced the daily food intake of obesity, but did not significantly reduce the weakness The amount of food intake per mouse (Fig. la). Although the energy intake decreased, Compound A increased the cumulative weight gain of obese rats (Fig. ib), but this weight gain was associated with an increase in protein increase (Fig. 2c The compound A did not affect the weight gain of the weak rats, but the total energy and fat increase decreased (Fig. 2a, b). The percentage of food efficiency in the weak rats also decreased (Fig. 2d). Demonstrate beneficial effects on obesity parameters such as total energy, fat increase, and food efficiency. Figures 3.a, 3.b, 3.c, 3.d, 3.e, 3.f, and 3.g The results of Test 2 were summed. Treatment with Compound A reduced circulating triglyceride content in weak rats (Fig. 3a). Compound A abolished fasting-induced plasma diglyceride reduction in obese rats. Esterified fatty acids (NEFA) increased, but Compound A attenuated this increase in obese rats (Fig. 3b). Reducing the plasma corticosterone content of lean rats and preventing the increase of fasting-induced corticosterone sputum in obese rats (Fig. 3c). The circulating glucose content in the compound rats treated with compound VIII was reduced to weak and Untreated fasted obese rats were similarly valued (Fig. 3d). Plasma glucose and insulin levels in fasting rats were used to calculate the homeostasis model of insulin resistance (h〇ma_ir) (Matthews et al. Although compound a did not significantly alter the blood-stamin content (Fig. 3e), the H〇MA_IR index decreased in obese rats (Fig. 3f). Both compound A and fasting reduced circulating leptin in weak rats. Content 119126.doc -29- 200812578 but did not reduce circulating leptin content in obese A rats (Fig. 3 g). These results, ie, the recovery of normal blood glucose and the H〇MA_ir index of insulin resistance in fat rats The decrease indicates improved insulin sensitivity, - prevents the increase in fasting-induced nefa and the decrease in fasting-induced triglyceride in obese rats, and the prosthetic A has a pair of metabolic syndrome (also known as insulin resistance). Related The beneficial effects of the pulp parameters. Compound A also reduces the increase in fasting-induced cortical solid secretion in obese atmosphere. “Hai Kou/Bai Yu is responsible for energy deposition and inhibits brown adipose tissue growth. Despite energy intake (daily food intake) A decrease in amount, but compound a increases the cumulative weight gain in obese rats associated with an increase in protein rather than an increase in fat. Thus, the compound of formula (1) of the present invention exhibits treatment or prevention of metabolic syndrome and/or obesity and/or abnormality. The beneficial effects of lipoprotein a. For the purpose of the intended use disclosed herein, a compound of formula (1) can be included as a active ingredient in a pharmaceutical composition. Such pharmaceutical compositions comprise an effective amount of a compound of the invention or an addition salt thereof with a pharmaceutically acceptable salt, or a hydrate or solvate of an addition salt, and at least one pharmaceutically acceptable Shape agent. These excipients are selected from the usual excipients known to those skilled in the art depending on the desired form of the drug and the route of administration. The pharmaceutical composition of the local month may contain - or a plurality of other activities which can be used for the treatment of the above disorders and diseases, while containing the compound of the formula (I). 119126.doc -30- 200812578 Ingredients. Accordingly, the present invention is also directed to a pharmaceutical composition comprising a compound of formula (I) of the present invention in combination with one or more active ingredient groups, the active ingredient being selected from one of the following therapeutic classes: - Cannabis test CBi receptor antagonist; - Cannabis CB2 receptor modulator; - AT! angiotensin π receptor antagonist; - Invertase inhibitor; - Calcium antagonist; - Li exhibit; - anti-high-fat ash or anti-hypercholesterolemia; - anti-diabetic agent; another anti-obesity agent or agent acting on metabolic disorders; ''ATiik tube vasopressin receptor antagonist" means Sartan _ (candesartan cilexetil), eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan a compound of valsartan, and each of the compounds of such compounds may be combined with a diuretic such as hydrochlorothiazide. The π-converting enzyme inhibitor π means, for example, alapril, benazepril. (benazepril) , captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril,赖普普利119126.doc -31 - 200812578 (lisinopril), moexipril, perindopril, quinapril, ramipril, snail Compounds of spirapril, temocapril, trandolapril, zofenopril, and the compounds of such compounds may themselves be associated with, for example, hydrogen thiazide or indapamide (indapamide) diuretic or in combination with a 13⁄4 antagonist such as amlodipine, diltiazem, felodipine or verapamil. "Calcium antagonist" means Amlodipine 'aranidipine, benidipine, bepridil, cilnidipine, diltiazem, efodipine hydrochloride ethanol, fashu Fasudil, Felodipine, isradipine, lacidipine, lercanidipine hydrochloride, manidipine, mibefradil Hydrochloride, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, tertalidipine Terodiline), a compound of verapamil. "β-blocker" means acebutolol, aprenolol, amosulalol, arotinolol, atenolol, Bifunolol, betaxolol, betaxolol, bevantolol, bisoprolol 119126.doc -32- 200812578 (bisoprolol), wave 11 bopindolol, buccolo (bucumolol), bufetolol, bunitolol, butofilolol, carazolol, carteolol, carvedilol ), cloralolol, epanolol, esmolol, indenolol, labetalol, landiolol, Levobunolol, levomoprolol, mepindolol, metipranolol, metoprolol, nadolol ), nebivolol, nifenalol, nipradilol, oxylenol Oxprenolol), penbutolol, pindolol, propranolol, salmeterol, sotalol, talinolol , tertalol, tilisolol, timolol, xamoterol, xibenolol compounds. ''Anti-hyperlipidemic or anti-hypercholesterolemia' means meaning from alumlbrate, beclobrate, bezaHbrate, ciprofibrate ), clinofibrate, cloflbrate, etofibrate, fenofibrate fiber esters; such as atorvastatin, fluvastatin sodium (Huvastatin) Sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, statin 119126.doc -33- 200812578 (statin) (HMG-C〇A reduction) a compound of an enzyme inhibitor, or such as acipimox, aluminium nicotinate, azacosterol, cholestyramine, dextrothyroxine, meige A compound of meglut〇l, niceritrol, nicoci〇nate, nicotinic acid, beta-sitosterol, tiadenol. "π anti-diabetic agent" means a compound belonging to one of the following types: sulfonylureas, biguanidines, alpha-glucose enzyme inhibitors, sputum dandrins, metiglinide , such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclaz Glcrazide, glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glyph Glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repligli Repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose, and membrane island And Tengdaosu analogues. "Other anti-obesity Or an agent acting on a metabolic disorder means "amfepramone, benfluorex, no. 119126.doc -34- 200812578 benzphetamine, indanorex , mazindol, mefenorex, methamphetamine, D-norpseudoephedrine, sibutramine, tortoise Topiramate compounds, lipase inhibitors (orlistat, cetiristat), PPAR agonists (peroxisome proliferator-activated receptor agonists), dopamine ( Dopamine) agonist, leptin receptor agonist, serotonin reuptake inhibitor, beta-3 agonist, CCK-A agonist, purine inhibitor, MC4 receptor agonist, MCH (melanin concentration) Hormone receptor antagonists, orexin antagonists, phosphodiesterase inhibitors, llpHSD (ll-p-hydroxysteroid dehydrogenase) inhibitors, DPP-IV (dipeptidyl peptidase IV) inhibition Agent, histamine H3 antagonist (or inverse agonist), CNTF (ciliary to neurotrophic factor) derivatives GHS (growth hormone secretagogue) receptor agonist, gastric hormone regulator, diglyceride thiol transferase (DGAT) inhibitor, phosphodiesterase (PDE) inhibitor, thyroid hormone agonist, sugar Corticosteroid receptor antagonist, stearyl-CoA-desaturase (SCD) inhibitor, phosphate, glucose, fatty acid or dicarboxylate transporter modulator, 5HT2 antagonist, 5HT6 antagonist, bell Bombesine agonist. According to the present invention, other compounds having anti-hyperlipemia, anti-cholesteric, anti-diabetic or anti-obesity properties may also be combined. More specifically, a compound belonging to one of the following types may be combined: PTP 1B (protein tyrosinate phosphatase-1B) inhibitor, VPAC-2 receptor agonist, GLK modulator, retinoid modulator, liver Glycophosphorylase 119126.doc -35- 200812578 (HGLPa) inhibitor, high blood serotonin antagonist, glucose phosphate inhibitor, propionate dehydrogenase kinase (PKD) activator, RXR, FXR, LXR regulation Agent, SGLT (sodium-dependent glucose transporter) inhibitor, CETP (cholesterol transfer protein) inhibitor, squalene synthetase inhibitor, • hornfishene epoxidase inhibitor, triglyceride synthesis inhibitor , LDL (Low Density Lipoprotein) Receptor Inducer, IBAT Inhibitor, FBPase (Fructose-Calcium Hydrochloride) Inhibitor, CART (Cocaine Amphetamine-Regulated Transcription) Regulatory f's Agent, MC4 (melanocortin 4 a modulator, an orexin receptor antagonist. According to another aspect of the present invention, one of the compounds of formula (I) or a solvate or hydrate thereof and other combined active ingredients may be administered simultaneously, separately or over time. ''Simultaneous use' means the administration of a compound of the composition of the invention contained in one and the same pharmaceutical form. "Use separately" means simultaneously administering two of the compositions of the invention each contained in a separate pharmaceutical form. Compound. "Used over time, means a continuous administration of a first compound of a composition of the invention in a pharmaceutical form, followed by a second compound of the composition of the present month in a separate pharmaceutical form." In this case, the time taken between the first compound administered the composition of the present invention and the second compound administered the same composition of the present invention is usually not more than 24 hours. For oral, sublingual, subcutaneous, The corresponding pharmaceutical composition for intramuscular, intravenous, topical, topical, intratracheal, intranasal, transdermal or rectal administration can be a single dosage form, and the active ingredient of the above formula (1) is blended with a common pharmaceutical excipient, The salt, solvate or hydrate thereof is administered to animals and humans at 119126.doc -36-200812578 for the prevention or treatment of the above diseases. The following ingredients are contained: The compound of the present invention 50.0 mg Mannitol 223.75 mg Crosslinked carboxymethyl fiber Sodium Sodium 6.0 mg Corn Starch 15.0 mg Hydroxypropyl Methyl Cellulose 2.25 mg Magnesium Stearate 3.0 mg By the oral administration of the dose of the active ingredient to be administered - or multiple shots Up to 0.5 to _ callout 'better' d2〇〇mg/kgo Suitable single-dose form contains oral forms such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, Oral, intratracheal, intraocular, intranasal, by inhalation, surface, transdermal, two: intramuscular or intravenous, rectal form and implant. For surface applications, the compounds of the invention may be used as a milk Cream, gel, ointment or lotion. A single dosage form of a compound of the invention in the form of a tablet in the form of a tablet may be included in the case of a special or lower dose, which may be appropriate. Within the scope of the invention, it is customary for the physician to determine the dosage appropriate for each patient based on the route of administration, the weight of the patient, and the response. 119126.doc -37-

Claims (1)

200812578 X. Patent application scope: 1 · A compound of formula (I) Its use as an addition salt, a hydrate thereof and/or a solvate thereof, which is used for U Manufacture of an agent intended to prevent or cure a metabolic syndrome, wherein -1 and 112 may be the same or different, each independently representing a halogen atom; a hydroxyl group (CVC5) alkyl group; (CVC5) alkyl group; an aralkyl group, wherein The base moiety is (C6-C8) and the alkyl moiety is (cvc4); (CVC5) alkoxy; trifluoromethyl; nitro; nitrile; -SR group, wherein R represents hydrogen, alkyl or aralkyl a group wherein the aryl moiety is (c6-c8) and the alkyl moiety is (Ci-C4); _S_CO-R is 15 wherein R represents (Ci-Cs)alkyl or arylalkyl wherein the aryl moiety is ( CrCs) and the alkyl moiety are (Cl_c4); -COORa group, wherein Ra represents hydrogen or (CVC5) alkyl; -CON RaRb group, wherein Ra and Rb are as defined above for Ra; _NRaRb group, wherein Ra and Rb is as defined above for Ra; _c〇NRcRd or -NRcRd group, wherein RC and Rd and the nitrogen atom to which they are attached constitute a 5- to 7-membered heterocyclic ring; or -NHCO-NRaRb group, wherein Ra and Rb are as above Ra Definitions; -R3 represents hydrogen or as defined in 1 and 112 above; 119126.doc 200812578 Alternatively, when I is substituted at the 5-position of the phenyl group, 1 and the heart constitute a -X_CH2_χ- group, wherein X Site represents CH2 or an oxygen or sulfur atom; _I represents (Cl-c6)alkyl; (Cl-C6)alkoxy (Ci_C3)alkyl; (cv c5)cycloalkyl; (c3-C6)cycloalkyl (CVC6)alkyl; (Ci-CJ alkaneite (Ci C3) alkyl, (Ci-C6) sulphoxy (Ci_C3) alkyl (Ci_C(5) alkylthio-oxyl (sulphodioxy)(C 1-C3)alkyl; R7 represents the group 'unsubstituted' at the 3, 4 or 5 position via halogen, via (Ci C; 5) alkyl, via -〇_CH2_0- group On two adjacent carbon atoms of the phenyl group, via -CF3, -N02 or -CN, via the group _COOR8 or •C〇NR8R9 or -CH2OR8, where r8&r9 represents (Cl_c3)alkyl, level OR10' Wherein r1〇 represents (Ci_c5) alkyl, mono-, di- or tri-substituted, or R7 represents °-specific, σ-septyl, σ-saltyl, sinyl, (C3-C5)cycloalkyl or (c3_C6) a cycloalkyl (CVC6) alkyl group. 2. The use of a compound of the formula (I) of claim 1 and an addition salt thereof, a hydrate thereof and/or a solvate thereof, for use in the manufacture of a prophylactic Or therapeutically treating the metabolic syndrome drug, wherein - heart and Han 2 may be the same or different, each alone Ground represents a halogen atom; C5) alkyl; (cvco alkoxy; -R3 represents hydrogen or as defined above by 1 and 112; -R6 represents (cvc6)alkyl; (CVC6) alkoxy ((VC3) alkane (c3_C5)cycloalkyl; (C3-C6)cycloalkylalkyl; -R7 represents phenyl which is unsubstituted or halogen at the 3 or 4 position, (Ci_C5) group '-CH2OR8 Wherein r8 represents (Ci-Cs)alkyl, or in 119126.doc 200812578 3, the 4-position is mono- or di-substituted via _〇-CH2_0•; or R7 represents (C3-C5)cycloalkyl. 3. The use of a compound of the formula (I) according to item 1 or 2, an addition salt thereof, a hydrate thereof and/or a solvate thereof, for the manufacture of a metabolic disorder intended for prophylactic or curative treatment Medicament wherein R3 is at the 5 position of the phenyl group. 4. The use of a compound of the formula (I) of claim 1 and an addition salt thereof, a hydrate thereof and/or a solvate thereof, for the manufacture of a medicament for the prophylactic or curative treatment of metabolic syndrome, wherein The compound of the formula (I) is selected from the group consisting of: -[4-(2-gas-4-methoxy-5-nonylphenyl)-5-methylthiazol-2-yl][(lR)-( L-(3-Fluoro-4-methylphenyl)-2-methoxyethyl)]prop-2-ynylamine hydrogenate, - [4-(2- gas-4-methoxy) -5-methylphenyl)-5-methylthiazol-2-yl] [(1S)-(1-phenylbutylpropan-2-ynylamine hydrogenate, -[4-(2-gas 4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1SH2-cyclopropyl_1_phenylethyl)]prop-2-ynylamine hydrogen acid Salt, -[4-(2-chloro-4-methoxyphenyl)_5-methylthiazole-2-yl][(lS)-(2-cyclopropyl-1-phenylethyl)]-propyl -2- alkynylamine hydrochloride, -[4·(2·Ga-4-methoxy-5-methylphenyl)_5-methylthiazol-2-yl] [(lS)-(2 -cyclopropyl 4-(4-fluorophenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4_(2- gas-4-methoxy-5-methylphenyl) -5-methylthiazole-2-yl][(1SH1-phenylpentyl)]prop-2-ynylamine Hydrogenate, -[4-(2-chloro-4-indoxy-5-fluorenylphenyl)-5-methylthiazol-2-yl] 119126.doc 200812578 [(1RM2-methoxy-1) -(4-methoxymethylphenyl)ethyl)]propan-2-ynylamine hydrogenate, -[4-(2-chloro-4-methoxy-5-methylphenyl)- 5-methylindole. Sodium-2-yl] [(IS)-(1-(4-methoxynonylphenyl)pentyl)]propan-2-ylamine hydrochloride, -[4 -(2-Ga-4-methoxy-5-methylphenyl)-5-methyl °嗤嗤-2-yl] [(1 S)_( 1 -(4-fluorophenyl)pentyl )]prop-2-ynylamine hydrochloride, -[4-(2-chloro-4-methoxy-5-methylphenyl)-5•methyl σ 嗤-2-yl] [ (lS)-(cyclopropylphenylindenyl)]prop-2-ynylamine hydrochloride, -[4-(2-chloro-4-methoxy-5-methylphenyl)-5 -methyl σ 嗤 嗤-2-yl] [(lS)-(l-(3-fluoro-4-methylphenyl)pentyl)]propan-2-ynylamine hydrochloride, -[4 -(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl] [(lS)-(2-cyclopropyl-1-(3-fluoro-4) -Methylphenyl)ethyl)]prop-2-ynylamine Hydrogenate, -[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazole- 2-yl][(1SH 1-(4-fluorophenyl)butyl)]-propyl 2-Alkynylamine Hydrogenate, -[4-(2-Chloro-4-indolyl-5.methylphenyl)-5-methylthiazol-2-yl] [(1SH1-(3- Fluoro-4-nonyloxynonylphenyl)butyl)]prop-2-ynylamine hydrochloride, -[4-(2-gas-4-methoxy-5-methylphenyl) -5-mercaptothiazol-2-yl] [(1SH2-cyclopropyl-1-(4-phenylphenyl)ethyl)]prop-2-ynylamine hydrogenate, [4-(2·chloro) 4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl] 119126.doc 200812578 [(1 S)-(2-cyclopropyl-1-(4-methylbenzene) Ethyl)]propynylamine hydrochloride, —[4-(2-Ga-4-methoxy-5-methylphenyl)-5-methyloxime~2·yl] [(18)-(2-Cyclobutyl-1-(4-fluorophenyl)ethyl)]propan-2-ynylamine hydrochloride, -[4-(2-Ga-4-methoxy) 5-(nonylphenyl)-5-methyl sedox-2-yl] [(lS)-(2-cyclopropyl-1-(4-bromophenyl)ethyl)]propane-2 - alkynylamine hydrochloride, -[4-(2-Ga-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl] [(1SM2-cyclopropyl- L-(3,4-Methylenedioxyphenyl)ethyl)]prop-2-ynylamine Hydrogenate, -[4-(2-Ga-4-methoxyphenyl)-5 -methylthiazol-2-yl][(lS)-(2-ring -1 -(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine hydrochloride, -[4-(2,4-dimethoxy-5-methyl Phenyl)-5-methylthiazol-2-yl][(1S)_(2-cyclopropyl4-(3-fluoro-4-indolylphenyl)ethyl)]propan-2-alkynylamine Hydrogenate, _ [4_(4-methoxy-2,5-dimethylphenyl)-5-methylthiazol-2-yl][(1S)-(2 里二基-1-(3 - gas _4_mercaptophenyl)ethyl)]prop-2-ynylamine hydrogenate, • ['(I gas-4-decyloxy-5-nonylphenyl)_5-mercaptothiazole Base] KiSHi_(3,4-methylenedioxyphenyl)butylpropynylamine hydrogenate. 5 · If the application of jg 1 , , is requested, wherein the compound of formula (I) is [4-(2- gas-4-indolylmethyl)-5-methylthiazole·2·yl][(is )-(2-cyclopropyl_ι_ 119126.doc 200812578 (3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine hydrochloride, used in the manufacture of a prophylactic or A therapeutic agent for the treatment of metabolic syndrome. 6. The use of a compound of the formula (1) according to any one of claims 1, 2, 3, 4 or 5, and an addition salt thereof, a hydrate thereof and/or a solvate thereof, for use in the manufacture of a prophylactic Or a cure for obesity. 7. The use of a compound of the formula (1) according to any one of claims 1, 2, 3, 4 or 5, and an addition salt thereof, a hydrate thereof and/or a solvate thereof, for use in the manufacture of a prophylactic Or a cure for the treatment of dyslipoproteinemia. 119126.doc